1. ¹Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA
2. ²Department of Psychiatry, Washington University, St Louis, MO, USA
3. ³Department of Psychology, Washington University, St Louis, MO, USA
4. ⁴Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
5. ⁵Department of Psychiatry, University of California-San Diego, San Diego, CA, USA
6. ⁶Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
7. ⁷Department of Genetics, Rutgers University, Piscataway, NJ, USA
8. ⁸Division of Child Psychiatry, University of Iowa Hospitals, Iowa City, IA, USA
9. ⁹Department of Psychiatry, SUNY Downstate Medical Center, Brooklyn, NY, USA

Correspondence: Dr X Xuei, PhD, Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 1345 W 16th St, Room 220, Indianapolis, IN 46202, USA. E-mail: xxuei@iupui.edu

Received 4 March 2006; Revised 19 July 2006; Accepted 24 July 2006; Published online 22 August 2006.

Abstract

Opioid receptors and their endogenous peptide ligands play important roles in the reward and reinforcement of drugs such as heroin, cocaine, and alcohol. The binding of dynorphins to the -opioid receptor has been shown to produce aversive states, which may prevent the development of reinforcement. We genotyped SNPs throughout OPRK1, encoding the -opioid receptor, and PDYN, which encodes its ligand prodynorphin, in a group of 1860 European American individuals from 219 multiplex alcohol dependent families. Family-based analyses demonstrated associations between alcohol dependence and multiple SNPs in the promoter and 3' end of PDYN, and in intron 2 of OPRK1. Haplotype analyses further supported the association of PDYN. Thus, variations in the genes encoding both the -opioid receptor and its ligand, OPRK1 and PDYN, are associated with the risk for alcohol dependence; this makes biological sense as variations in either should affect signaling through the -opioid system.